US4591585A - 1-alkyl-androsta-1,4-diene-3,17-diones their production and pharmaceutical preparations containing same - Google Patents
1-alkyl-androsta-1,4-diene-3,17-diones their production and pharmaceutical preparations containing same Download PDFInfo
- Publication number
- US4591585A US4591585A US06/621,769 US62176984A US4591585A US 4591585 A US4591585 A US 4591585A US 62176984 A US62176984 A US 62176984A US 4591585 A US4591585 A US 4591585A
- Authority
- US
- United States
- Prior art keywords
- compound
- diene
- dione
- androsta
- diones
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
Links
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- 239000000600 sorbitol Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J1/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane
- C07J1/0003—Androstane derivatives
- C07J1/0011—Androstane derivatives substituted in position 17 by a keto group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- This invention relates to 1-alkyl-androsta-1,4-diene-3,17-diones of general Formula I, to processes for the production and use thereof, and to pharmaceutical preparations containing them.
- this invention relates to 1-alkyl-androsta-1,4-diene-3,17-diones of the Formula ##STR2## wherein R 1 is a methyl, ethyl, hydroxymethyl, C 1 -C 3 -alkoxymethyl or C 1 -C 4 -alkanoyloxymethyl; R 6 is a hydrogen atom or methyl; and R 7 is a hydrogen atom or methyl.
- this invention relates to pharmaceutical compositions comprising a compound of Formula I in admixture with a pharmaceutically acceptable carrier.
- this invention relates to methods for the production of the 1-alkyl steroids of this invention.
- this invention relates to the use of the compounds of this invention as aromatase-inhibitors.
- R 6 and R 7 are H and the other is CH 3 , especially those wherein R 7 is CH 3 ;
- R 1 is CH 3 , including those of groups (a) and (b);
- R 1 is HOCH 2 , including those of groups (a) and (b);
- R 1 is CH 3 OCH 2 , including those of groups (a) and (b);
- R 1 is CH 3 COOCH 2 , including those of groups (a) and (b).
- R 1 ether groups are methoxymethyl, ethoxymethyl and straight and branched chain propyloxymethyl and butyloxymethyl.
- R 1 ester groups are formyloxymethyl, acetoxymethyl and straight and branched chained propionyloxymethyl and butyryloxymethyl.
- novel compounds of general Formula I inhibit estrogen biosynthesis, which is surprising, since the corresponding androsta-1,4-diene-3,17-diones which are unsubstituted in the 1-position cause a marked rise in the estrogen level.
- aromatase is the speed-regulating enzyme in the conversion of androstenedione and testosterone into estrone and estradiol.
- A 4-Hydroxy-4-androstene-3,17-dione (as a comparison compound in testing for aromatase-inhibiting effect, estrogenic activity, and in the testicle inhibition test).
- test compounds A, B, C, and D The influence exerted by test compounds A, B, C, and D on the PMSG (pregnant mare's serum gonadotropin)-stimulated estrogen production was investigated.
- the secretion of estradiol increased by treatment with PMSG (control), can be reduced by administration of aromatase inhibitors.
- Variance analysis was used to check the significance of the differences with respect to the control group.
- the strength of efficacy was determined by regression/covariance analysis.
- Ovariectomized rats 200 g and mice (30 g), respectively, received subcutaneous administrations of the test compound once daily for 5 days.
- the control animals received only the vehicle.
- the average value for the organ weight and the standard deviation were determined for each group. The significance of the differences as compared with the control group was examined by variance analysis.
- Compound B of this invention (3 and 10 mg/animal/day, 5 ⁇ s.c.) does not evoke estrogenic activity either in rats or mice (Tables 2 and 3). Comparison compound A, in contrast thereto, leads to a significant increase in weights of the uteri with a dosage of 3 and 10 mg/animal/day (5 ⁇ s.c.).
- Testicle Inhibition Test In Rats to Determine Antigonadotropic Activity
- Infantile male rats (30 g) were treated once daily for 12 days with the test compound by subcutaneous administration. One day after the final treatment, the animals were sacrificed and the testes were weighed. The control animals received only the vehicle.
- the organ weights of the prostates, seminal vesicles, and adrenal glands were determined.
- the organ weights were converted to mg/100 g body weight. For each group, the average value and the standard deviation were calculated.
- compound B of this invention shows, no effect on the testicle weights (no antigonadotropin activity) but produces, at a dosage of 1 mg/animal/day, a slight reduction in seminal vesicle weights.
- comparison compound A produces a significant reduction in the organ weights of the testicles, seminal vesicles and adrenal glands.
- compound B of this invention has no effect on the fresh weights of seminal vesicles, prostate, m. [musculus]levator ani, and adrenal glands.
- the novel compounds of general Formula I are suitable for inhibiting estrogen biosynthesis and consequently for the treatment of diseases caused by or dependent upon estrogens.
- estrogen For example, an excess of estrogen is frequently found in women who are in menopause, with the associated risk of contracting breast cancer. In men, increased estrogen production and a raised estrogen/androgen ratio leads to gynecomastia and hyperplasia of the prostate.
- the compounds are suitable for treatment of breast cancer and other estrogen-induced or -stimulated tumors.
- aromatase inhibitors they are also advantageously suited for prophylactic and/or therapeutic treatment of prostate hyperplasia, as described, e.g., in U.S. Ser. Nos. 448,672 and 448,673, both filed on Dec. 10, 1982, and both of whose disclosures are incorporated by reference herein.
- novel compounds are also valuable for affecting fertility, for example for treatment of male infertility resulting from elevated estrogen levels.
- the compounds can be utilized as antifertility agents, e.g., to prevent ovulation or implantation in women of childbearing age.
- the compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously, or percutaneously.
- the compounds can also be implanted in tissue.
- the amount of compound to be administered varies within a wide range and can cover any effective quantity. Depending on the condition to be treated and the method of administration, the amount of compound administered can be 0.01-100 mg/kg body weight, preferably 0.1-20 mg/kg body weight, per day.
- the dosage units can contain, besides the active ingredient, a pharmaceutically acceptable excipient, such as, for example, amylose, sugar, sorbitol, gelatin, lubricants, silicic acid, talc, etc.
- a pharmaceutically acceptable excipient such as, for example, amylose, sugar, sorbitol, gelatin, lubricants, silicic acid, talc, etc.
- the individual dosage units for oral administration can contain, for example, 10-100 mg of the active agent (aromatase inhibitor).
- the active agents can be dissolved or suspended in a physiologically compatible diluent.
- Oils with or without the addition of a solubilizer, are utilized very frequently as the diluents. Examples for oils that are utilized are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil.
- the compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated so that timed release of active compound is made possible.
- Implants can contain, as the inert materials, for example, biologically degradable polymers or synthetic silicones, e.g., silicone rubber.
- the active agents furthermore can be incorporated into a plaster for percutaneous administration.
- This invention in one aspect, relates to pharmaceutical preparations containing a compound of general Formula I.
- novel compounds of general Formula I can be produced according to the following reaction schemes:
- Reactions (a) through (d) take place according to known methods of steroid chemistry.
- the oxidation set forth in process version (a) can be conducted in a manner known per se, for example with chromic acid reagents (Jones' reagent or chromic acid-pyridine) or with pyridinium dichromate or chlorochromate.
- the 1,2-dehydrogenation according to process (b) can take place by means of known methods with dehydrogenation agents such as selenium dioxide or dichlorodicyanobenzoquinone.
- Double bonds in the 1,2- and 4,5-positions can be introduced simultaneously, for example by bromination to the 2,4-dibromo-3-ketone and dehydrobromination of the dibromide with lithium carbonate or calcium carbonate and lithium bromide in dimethylformamide.
- a 1-hydroxymethyl group liberated during the reaction can subsequently be esterified or etherified, and a liberated 17-hydroxy group can subsequently be oxidized.
- Esterification of the 1-hydroxymethyl group in the presence of a 17-hydroxy group takes place preferably with lead diacetate and acetic anhydride in dimethylformamide.
- Oxidation of the 17 ⁇ -hydroxy group is accomplished by following process version (a).
- the chemical dehydrogenation agents as well as microbiological dehydrogenation can be employed.
- Suitable microorganisms for introduction of the 1,2- and 4,5-double bonds are, for example, schizomycetes, for example Arthrobacter simplex (ATCC 6946), Bacillus lentus (ATCC 13805), or Bacillus sphaericus (ATCC 7055).
- Saponification of a 1-alkanoyloxymethyl group according to process (d) can take place with an inorganic base in an alcoholic solution and the optionally subsequent reesterification is preferably conducted with the corresponding acid anhydride in the presence of organic bases.
- a preferred embodiment provides to react the 1-hydroxymethyl steroid with p-toluenesulfonic acid chloride and pyridine to the 1-tosyloxymethyl steroid, and then with alkali alcoholate to the 1-alkoxymethyl steroid.
- Contemplated equivalents of the compounds of this invention are aromatase inhibiting compounds otherwise corresponding to those of Formula I wherein R 1 is a hydroxymethyl group esterified or etherified with another ester or ether group, e.g., higher alkoxy or alkanoyloxy.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Steroid Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE3322285A DE3322285A1 (de) | 1983-06-18 | 1983-06-18 | 1-alkyl-androsta-1,4-dien-3,17-dione, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate |
| DE3322285 | 1983-06-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4591585A true US4591585A (en) | 1986-05-27 |
Family
ID=6201972
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/621,769 Expired - Lifetime US4591585A (en) | 1983-06-18 | 1984-06-18 | 1-alkyl-androsta-1,4-diene-3,17-diones their production and pharmaceutical preparations containing same |
Country Status (19)
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4808616A (en) * | 1985-07-09 | 1989-02-28 | Farmitalia Carlo Erba S.R.L. | 6-substituted androsta-1,4-diene-3,17-diones |
| US4824830A (en) * | 1986-07-14 | 1989-04-25 | Farmitalia Carlo Erba S.R.L. | 6- or 7-methylenandrosta-1,4-diene-3,17-dione derivatives and process for their preparation |
| US4871482A (en) * | 1987-05-07 | 1989-10-03 | Schering Aktiengesellschaft | Process for the preparation of 1-methylandrosta-1,4-diene-3,17,dione, and the novel intermediates for this process |
| US5047757A (en) * | 1987-09-04 | 1991-09-10 | Stc Plc | Method of addressing a ferroelectric liquid crystal display |
| WO1992017489A1 (en) * | 1991-03-28 | 1992-10-15 | Teikoku Hormone Mfg. Co., Ltd. | Novel oxa- or azasteroid derivative |
| US5275936A (en) * | 1985-04-03 | 1994-01-04 | Schering Aktiengesellschaft | Process for the preparation of 1-methyl-1,4-androstadiene-3,17-dione |
| US5539127A (en) * | 1992-09-30 | 1996-07-23 | Teikoku Hormone Mfg. Co., Ltd. | 7-substituted oxa- or azasteroid compound |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3512328A1 (de) * | 1985-04-03 | 1987-03-19 | Schering Ag | Verahren zur herstellung von 1-methyl-1,4-androstadien-3,17-dion |
| DE3539244A1 (de) * | 1985-11-01 | 1987-05-07 | Schering Ag | 1-methyl-15(alpha)-alkyl-androsta- 1,4-dien-3,17-dione, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate |
| DE3703722A1 (de) * | 1987-02-04 | 1988-08-18 | Schering Ag | 1-methyl-15(alpha)-(1,2-dialkanoyloxyalkyl)-androsta-1,4-dien-3,17-dione, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate |
| DE3705990A1 (de) * | 1987-02-20 | 1988-09-01 | Schering Ag | 1-methyl-15(alpha)-(1-oxyalkyl)-androsta-1,4-dien- 3,17-dione, verfahren zu deren herstellung und diese enthaltende pharmazeutische praeparate |
| EP0310542B1 (de) * | 1987-10-01 | 1994-06-08 | Schering Aktiengesellschaft | Antigestagen- und antiöstrogenwirksame Verbindungen zur Behandlung hormonabhängiger Tumoren |
| GB9222669D0 (en) * | 1992-10-28 | 1992-12-09 | Erba Carlo Spa | 6,7 alpha-difluoromethylenandrosta-1,4-dien-3-one derivatives and process for their preparation |
| DE4435368A1 (de) * | 1994-09-22 | 1996-03-28 | Schering Ag | Verwendung von Aromatasehemmern zur Herstellung eines Arzneimittels zur Behandlung eines relativen Androgenmangels beim Mann |
| WO1996015253A1 (de) * | 1994-11-14 | 1996-05-23 | Schering Aktiengesellschaft | Verfahren zur herstellung von 1-hydroxymethyl-1.4-androstadien-3.17-dion |
| ZA9510926B (en) | 1994-12-23 | 1996-07-03 | Schering Ag | Compounds with progesterone-antagonistic and antiestrogenic action to be used together for female contraception |
| EP0943333A1 (de) * | 1998-03-18 | 1999-09-22 | S.W. Patentverwertungs GmbH | Medikament zur Prophylaxe und/oder Behandlung des Mammakarzinoms enthaltend einen Hemmer der Bildung von Oestrogenen |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4456600A (en) * | 1979-10-26 | 1984-06-26 | Schering, Aktiengesellschaft (A.G.) | Antiandrogenic 17α-alkyl steroids |
| US4474701A (en) * | 1983-03-10 | 1984-10-02 | Veb Jenapharm Jena | Process for the separation of 4-androsten-3,17-dione and 1,4-androstadien-3,17-dione |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3006929A (en) * | 1957-09-24 | 1961-10-31 | Searle & Co | 1-methyl-17-alkyl-19-nortestosterones |
| DE1174776B (de) * | 1962-08-04 | 1964-07-30 | Schering Ag | Verfahren zur Herstellung von 1ª‡, 7ª‡-Dimethyl-steroiden der Androstanreihe |
| DE1174778B (de) * | 1962-08-16 | 1964-07-30 | Schering Ag | Verfahren zur Herstellung von 3, 4-Dimethyl-?-oestratrien-1, 17ª‰-diol |
| DE1249268B (de) * | 1964-12-02 | 1967-09-07 | Schermg Aktiengesellschaft, Berlin | Verfahren zur Herstellung von 1 7a-Dimethyl - A1 - androstcnolondenvaten |
-
1983
- 1983-06-18 DE DE3322285A patent/DE3322285A1/de not_active Withdrawn
-
1984
- 1984-06-08 DK DK282784A patent/DK158358C/da not_active IP Right Cessation
- 1984-06-08 ES ES533261A patent/ES8502709A1/es not_active Expired
- 1984-06-10 IL IL72067A patent/IL72067A/xx unknown
- 1984-06-13 AT AT84730063T patent/ATE28752T1/de not_active IP Right Cessation
- 1984-06-13 EP EP84730063A patent/EP0129500B1/de not_active Expired
- 1984-06-13 DE DE8484730063T patent/DE3465201D1/de not_active Expired
- 1984-06-15 IE IE1494/84A patent/IE57621B1/en not_active IP Right Cessation
- 1984-06-15 DD DD84264192A patent/DD218623A5/de not_active IP Right Cessation
- 1984-06-15 CA CA000456730A patent/CA1223251A/en not_active Expired
- 1984-06-15 NO NO842408A patent/NO159278C/no not_active IP Right Cessation
- 1984-06-15 GR GR75032A patent/GR82160B/el unknown
- 1984-06-15 HU HU842322A patent/HU189415B/hu unknown
- 1984-06-15 AU AU29399/84A patent/AU562646B2/en not_active Expired
- 1984-06-15 PT PT78743A patent/PT78743B/pt unknown
- 1984-06-18 US US06/621,769 patent/US4591585A/en not_active Expired - Lifetime
- 1984-06-18 FI FI842457A patent/FI81361C/fi not_active IP Right Cessation
- 1984-06-18 NZ NZ208552A patent/NZ208552A/en unknown
- 1984-06-18 ZA ZA844603A patent/ZA844603B/xx unknown
- 1984-06-18 JP JP59123911A patent/JPS6013796A/ja active Granted
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4456600A (en) * | 1979-10-26 | 1984-06-26 | Schering, Aktiengesellschaft (A.G.) | Antiandrogenic 17α-alkyl steroids |
| US4474701A (en) * | 1983-03-10 | 1984-10-02 | Veb Jenapharm Jena | Process for the separation of 4-androsten-3,17-dione and 1,4-androstadien-3,17-dione |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5275936A (en) * | 1985-04-03 | 1994-01-04 | Schering Aktiengesellschaft | Process for the preparation of 1-methyl-1,4-androstadiene-3,17-dione |
| US4808616A (en) * | 1985-07-09 | 1989-02-28 | Farmitalia Carlo Erba S.R.L. | 6-substituted androsta-1,4-diene-3,17-diones |
| US4904650A (en) * | 1985-07-09 | 1990-02-27 | Farmitalia Carlo Erba S.P.A. | Substituted androsta-1,4-diene-3,17-diones |
| US4824830A (en) * | 1986-07-14 | 1989-04-25 | Farmitalia Carlo Erba S.R.L. | 6- or 7-methylenandrosta-1,4-diene-3,17-dione derivatives and process for their preparation |
| US4871482A (en) * | 1987-05-07 | 1989-10-03 | Schering Aktiengesellschaft | Process for the preparation of 1-methylandrosta-1,4-diene-3,17,dione, and the novel intermediates for this process |
| US5047757A (en) * | 1987-09-04 | 1991-09-10 | Stc Plc | Method of addressing a ferroelectric liquid crystal display |
| WO1992017489A1 (en) * | 1991-03-28 | 1992-10-15 | Teikoku Hormone Mfg. Co., Ltd. | Novel oxa- or azasteroid derivative |
| US5519051A (en) * | 1991-03-28 | 1996-05-21 | Teikoku Hormone Mfg. Co., Ltd. | Oxa- or azasteroid derivatives |
| US5539127A (en) * | 1992-09-30 | 1996-07-23 | Teikoku Hormone Mfg. Co., Ltd. | 7-substituted oxa- or azasteroid compound |
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